Seventy-four percent of all anti-cancer drugs produced over the last two decades have found their origin in natural products. Cortistatin A, below, is a marine steroid with highly selective, and
perhaps mechanistically unique anti-angiogenic activity. Owing to its remarkable pharmacological potential a number of efforts across the world have been devoted to procuring useful quantities of cortistatin A through chemical synthesis.
Steroids have historically elicited attention from the chemical sciences owing to their utility in living systems, as well as their intrinsic and diverse beauty [C. Djerassi, “Steroids Made it Possible”. In Profiles, Pathways and Dreams; Seeman, J. I., Ed. (American Chemical Society: Washington, D.C., 1990)]. The cortistatin family (cortistatin A-L;
above, Compounds I-7 and others) [Aoki et al., J. Am. Chem. Soc. 128, 3148 (2006); Watanabe et al., Tetrahedron 63, 4074 (2007); Aoki et al., Tetrahedron Lett. 48, 4485 (2007)], a collection of unusual, marine 9(10-19)-abeo-androstane steroids, is certainly no exception: aside from challenging stereochemistry and an odd bricolage of functional groups, the salient feature of these sponge metabolites is, inescapably, their biological activity.
Cortistatin A, the most potent member of the small family, inhibits the proliferation of human umbilical vein endothelial cells (HUVECs, IC50=1.8 nM), evidently with no general toxicity toward either healthy or cancerous cell lines (IC50 (testing cells)/IC50 (HUVECs)≧3300) [Aoki et al., J. Am. Chem. Soc. 128, 3148 (2006)]. From initial pharmacological studies, binding appears to occur reversibly, but to an unknown target, inhibiting the phosphorylation of an unidentified 110 kDa protein, and implying a pathway that may be unique to known anti-angiogenesis compounds [Aoki et al., Bioorganic & Medicinal Chemistry 15, 6758 (2007)].
Since the isolation of the first angiogenesis inhibitors [Taylor et al., Nature 297, 307 (1982)] and growth factors [Shing et al., Science 1984, 223, 1296] in the Folkman laboratories over 25 years ago, pathological angiogenesis has become recognized as an ‘organizing principle’ for understanding a variety of otherwise disparate disorders [Folkman, Nature Reviews Drug Discovery 6, 273 (2007)]. The most familiar application of anti-angiogenesis therapy effects the regression of solid tumors, where inhibitors are responsible for both direct anti-tumor activity [Folkman, in Holland Frei—Cancer Medicine 7, D. W. Kufe et al., Eds., (American Association for Cancer Research, B. C. Decker, Hamilton, Ontario, Canada, ed. 7, 2006), pp. 157-191; Folkman, in Accomplishments in Cancer Research, Wells et al., Eds. (Lippincott Williams & Wilkins, New York, 1998) pp. 32-44], and increased chemotherapeutic uptake through vascular in the clinic [Satchi-Fainaro et al., Cancer Cell. 7, 251 (2005)], prompting further exploration of both terrestrial and marine environments [Aoki et al., J. Am. Chem. Soc. 128, 3148 (2006)]. However, access to sufficient quantities of marine macro-organism natural products—the cortistatins, for instance, were isolated from the marine sponge Corticium simplex—is generally impeded by prohibitively expensive isolation work and ecological considerations [Newman et al., Curr. Med. Chem. 11, 1693 (2004); Marris, Nature 443, 914 (2006)], thus necessitating chemical synthesis.
Compelled by the pharmacological potential of the cortistatins [Aoki et al., Bioorganic & Medicinal Chemistry 15, 6758 (2007); Carmeliet, Nature 438, 932 (2005)] together with the unanswered questions surrounding their biological activity, we embarked on a synthesis of cortistatin A [C. Djerassi, “Steroids Made it Possible”. In Profiles, Pathways and Dreams; Seeman, J. I., Ed. (American Chemical Society: Washington, D.C., 1990)], aiming for a concise route from inexpensive, commercially available materials, and the opportunity to develop new chemistry as the occasion arose. Corollary to these goals was our group's ongoing interest in minimizing functional group interconversions (FGIs) [Corey et al., The Logic of Chemical Synthesis (Wiley, New York, 1995] through a diminished reliance on protecting groups [Maimone et al., Nature 446, 404 (2007)].
The disclosure that follows provides the first synthesis of this natural product and related analogues. This synthesis proceeds by way of ‘cortistatinone,’ an intermediate ideally suited for investigating the key pharmacophore of the cortistatin family.